Naringenin ameliorates hypoxia/reoxygenation-induced endoplasmic reticulum stress-mediated apoptosis in H9c2 myocardial cells: involvement in ATF6, IRE1[alpha] and PERK signaling activation

• Published in: Molecular and cellular biochemistry Vol. 424; no. 1-2; p. 111
• Main Authors: Tang, Jia-You, Jin, Ping, He, Qing, Lu, Lin-He, Ma, Ji-Peng, Gao, Wei-Lun, Bai, He-Ping, Yang, Jian
• Format: Journal Article
• Language: English
• Published: New York Springer 01.01.2017; Springer Nature B.V
• Subjects: Apoptosis; Cardiovascular diseases; Citrus fruits; Cytotoxicity; Health aspects; Heart; Hypoxia; Injuries; Protein kinases; Proteins; Stress
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-016-2848-1

Naringenin, a flavanone mainly derived from grapes and citrus fruits, has been reported to exhibit cardioprotective effects. Accumulating evidence has confirmed that endoplasmic reticulum (ER) stress-mediated apoptosis participates in the process of myocardial ischemia/reperfusion injury and inhibiting ER stress is a potential therapeutic target/strategy in preventing cardiovascular diseases. Herein, the current study was designed to investigate whether naringenin protects H9c2 myocardial cells against hypoxia/reoxygenation (H/R) injury via attenuating ER stress or ER stress-mediated apoptosis. Our results showed that naringenin treatment resulted in obvious increases in the viability of H9c2 cells and the expression of Bcl-2 (anti-apoptotic protein), and decreases in the morphological changes of apoptotic cells, the activity of caspase-3 and the expression of Bax (pro-apoptotic protein) in H/R-treated H9c2 cells, implying the protective effects of naringenin against H/R-induced injury. In addition, naringenin also significantly reversed H/R-induced ER stress as evidenced by the up-regulation of Glucose-regulated protein 78, C/EBP homologous protein and Cleaved caspase-12 proteins. Meanwhile, naringenin remarkably reversed H/R-induced the increases in the expression of cleaved activating transcription factor 6 (ATF6) and phosphorylation levels of phospho-extracellular regulated protein kinases (PERK) and inositol-requiring enzyme-1[alpha] (IRE1[alpha]) in H9c2 cells. Finally, we found that ATF6 siRNA, PERK siRNA or IRE1[alpha] siRNA abolished H/R-induced cytotoxicity and apoptosis in H9c2 cells. In conclusion, these results confirmed that ER stress-mediated apoptosis contributes to the protection effects of naringenin against H/R injury, which is potentially involved in ATF6, IRE1[alpha] and PERK signaling activation.